289
GUEST EDITORIAL
Keratoconus and corneal crosslinking
Theo Seiler, MD, PhD
Zurich, Switzerland
This guest editorial is one of a series looking back at
landmark articles published in the JCRS. This special
series commemorates the 25th anniversary of the
joint Journal of Cataract & Refractive Surgery. This
Downloaded from http://journals.lww.com/jcrs by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 03/04/2021
issue: Stress–strain measurements of human and
porcine corneas after riboflavin-ultraviolet-A-induced
crosslinking. J Cataract Refract Surg 2003;29:1780–1785.
During the past 40 years, 2 main causes for keratoconus
have been identified: eye rubbing and reduced bio-
mechanical stiffness of the cornea. The coincidence of
keratoconus and atopic conjunctivitis was described al-
ready 100 years ago, but it took another 50 years to un-
derstand that it is the mechanical trauma to the connective
tissue eye shell that induces ectasia.1,2 Intraocular pressure
spikes of up to 300 mm Hg accompany eye rubbing and
lead to extension of cornea and sclera, both viscoelastic
tissues.3 Although some hardliners of the eye rubbing
hypothesis advocate this as the only cause of keratectasia
(no rubbing—no conus), we have good reasons to believe
that pathology processes other than rubbing are involved in
the progression of keratectasia: (1) we have many kera-
toconus patients who never had episodes of eye rubbing, (2)
keratoconus is a bilateral disease, but eye rubbing is in
approximately 50% of the cases single handed, and the
association between patient-reported unilateral eye rubbing
and greater asymmetry in corneal curvature (steep
K-reading) is weak, and (3) sclera is more viscous than
cornea, and therefore, we would expect a stronger effect on
scleral extension than on cornea; however, to my knowl-
edge, an effect of eye rubbing on myopia progression has
not been reported so far.4,5
Increased elasticity (reduced stiffness) of keratoconus
cornea compared with normal cornea was reported by
Andreassen et al in 1980, and Edmund found in 1988 a
significantly reduced Young modulus of the cornea in
keratoconus eyes.6,7 The ocular rigidity coefficient de-
scribing scleral and corneal biomechanical expansion,
however, did not differ between normal and keratoconus
eyes.8 In addition, modern methods of measuring ocular
rigidity such as the ocular response analyzer primarily
failed to discriminate between keratoconus and normal
eyes.
Based on these considerations, we established the
working hypothesis that eye rubbing and reduced bio-
mechanical stiffness of the cornea contribute interactively
to the genesis of keratoconus. The proportion of each causal
mechanism may vary significantly from patient to patient,
Copyright © 2021 Published by Wolters Kluwer on behalf of ASCRS and ESCRS
Published by Wolters Kluwer Health, Inc.
Copyright © 2021 Published by Wolters Kluwer on behalf of ASCRS and ESCRS. Unauthorized reproduction of this article is prohibited.
and we may find strong rubbers with normal corneas and
no rubbers with weak corneas both ending up in pro-
gressive keratoconus. By means of in vivo Brillouin spec-
troscopy, we measured a high variation of the corneal bulk
modulus in nonkeratoconus eyes even higher than the
average difference between 20- and 60-year-old corneas.9
This surprising result supports the working hypothesis and
requests of any modern therapy of keratoconus to address
both causal arms: stiffening of the cornea and to stop
rubbing by means of topical treatment of the itching eye.
The landmark article on elasticity of crosslinked human
cornea (and previous papers in German) covered the
biomechanical arm of keratoconus therapy only.10 It
documents convincingly that, by means of corneal cross-
linking (CXL) using the Dresden protocol, the stiffness of
the human cornea can be enhanced significantly. Although,
at first glance, this looks impressive, a one treatment fits all,
however, may lead to overcrosslinked and undercrosslinked
corneas. Undercrosslinked corneas continue to progress
and such treatment failures were reported in 4% to 10% of
the cases. On the other hand, in less than 10% of the
crosslinked corneas a too strong effect of CXL was found
leading to continued flattening of the cornea with a con-
stant flattening rate for more than 10 years.11 We in-
terpreted this as a consequence of overcrosslinking. Such a
mismatch of achieved vs required CXL could be easily
avoided by choosing the right irradiation time to obtain a
certain radiant exposure (in J/cm2). If we only would know
how much CXL a cornea needs to achieve normal stiffness!
A preoperative determination of the biomechanical pa-
rameters by means of clinical Brillouin spectroscopy or
other elastometric techniques was necessary to customize
the amount of CXL.
The landmark article was the starting signal for a series of
publications on CXL that accumulated until today to more
than 2500 clinical and basic science articles (PubMed re-
search January 2021).10 The 2-layer model proposed in the
article was verified clinically a few years later by the de-
marcation line visible at the slitlamp or in anterior segment
optical coherence tomography.12 Meanwhile, we also
learned that it is not only riboflavin and ultraviolet A that
determines the success of CXL but also the intrastromal
oxygen that represents the bottleneck of clinical CXL and
limits the applicability of accelerated CXL.13 Despite some
improvements of CXL, the parameters 5.4 J/cm2 for radiant
exposure and 0.1% of riboflavin concentration are still valid
today and are used in most of the hundreds of thousands of
clinical treatments across the world.
0886-3350/$ - see frontmatter
https://doi.org/10.1097/j.jcrs.0000000000000591
290 GUEST EDITORIAL

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First author:
Theo Seiler, MD, PhD
Zurich, Switzerland

Volume 47 Issue 3 March 2021

Copyright © 2021 Published by Wolters Kluwer on behalf of ASCRS and ESCRS. Unauthorized reproduction of this article is prohibited.